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Real-time analysis of shear-dependent thrombus formation and its blockade
by inhibitors of von Willebrand factor binding to platelets
BR Alevriadou, JL Moake, NA Turner, ZM Ruggeri, BJ Folie, MD Phillips, AB Schreiber, ME Hrinda and LV McIntire
Cox Laboratory for Biomedical Engineering, Rice University, Houston, TX
77251.
Two likely mechanisms for the initiation of arterial platelet thrombus
formation under conditions of elevated fluid shear stresses are: (1)
excessive adhesion and aggregation of platelets from rapidly flowing blood
onto the exposed sub-endothelium of injured, atherosclerotic arteries; or
(2) direct, fluid shear stress-induced aggregation of platelets in
constricted arteries with intact endothelial cells. Mechanism (1) was
simulated using a parallel plate flow chamber, fibrillar collagen type
I-coated slides, and mepacrine-labeled (fluorescent) platelets in whole
blood anticoagulated with citrate, hirudin, unfractionated porcine heparin,
or low molecular weight heparin flowing for 1 to 2 minutes at wall shear
rates of 100 to 3,000 seconds-1 (4 to 120 dynes/cm2). The precise sequence
of interactions among von Willebrand factor (vWF), glycoprotein (GP)Ib, and
GPIIb-IIIa during platelet adhesion and subsequent aggregation were
resolved by direct real-time observation using a computerized
epifluorescence video microscopy system. Adhesion at high shear rates was
the result of the adsorption of large vWF multimers onto collagen and the
binding of platelet GPIb to the insolubilized vWF. Aggregation occurred
subsequently and required the binding of ligands, including vWF via its RGD
binding domain, to GPIIb-IIIa. Mechanism (2) was modeled by producing shear
stresses of 90 to 180 dynes/cm2 in a rotational cone and plate viscometer,
which aggregates platelets from platelet-rich- plasma (PRP) anti-coagulated
with citrate, hirudin, or either type of heparin in reactions that require
large vWF multimers, Ca2+, adenosine diphosphate, and both GPIb and
GPIIb-IIIa. Both vWF-mediated shear- aggregation in PRP and
platelet-collagen adhesion in flowing whole blood (anticoagulated with
citrate and hirudin) are inhibited by two potentially useful anti-arterial
thrombotic agents: polymeric aurin tricarboxylic acid (ATA; 28.5 to 114
micrograms/mL), which binds to vWF and inhibits its attachment of GPIb, and
a recombinant vWF fragment (rvWF445-733; 30 to 200 micrograms/mL) that
binds to platelet GPIb (in the absence of any modulator) and blocks
attachment of vWF multimers. Unfractionated heparin, but not low molecular
weight heparin, apparently binds to rvWF445-733 and counteracts the
inhibitory effects of the vWF fragment in vitro on shear-aggregation and
platelet-collagen adhesion.
Volume 81,
Issue 5,
pp. 1263-1276,
03/01/1993
Copyright © 1993 by The American Society of Hematology
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